Recent neuropathology studies have provided compelling evidence that neurofibrillary tangles, a major pathologic feature of Alzheimer's disease (AD), are closely associated with neuronal death and volume reductions. These lesions appear to show an orderly progression in the brain. Perirhinal and entorhinal cortex (EC) may be the first affected, followed by the hippocampus, and later the temporal lobe neocortex. Our neuroimaging results during the current funding period are largely in agreement with this pattern. We observed an anatomically specific hippocampal volume loss that accurately distinguished between normal aging and mild cognitive impairment (MCI) patients. Moreover, baseline hippocampal size predicted memory declines in both groups at 4 year follow-up. We observed that accurate classification of MCI and AD patients required both hippocampal and lateral temporal lobe volume measures. These results suggest a progression of changes that may be characterized by 2 stages of clinico-anatomic pathology: a hippocampal atrophy stage associated with MCI followed by a neocortical atrophy stage with overt dementia. Our proposed study will attempt to reveal the existence of an earlier stage of AD related pathology, marked by EC atrophy and mild memory changes. We specifically hypothesize that in normal elderly EC atrophy is an anatomically unique predictor of future reductions in hippocampal size, memory impairment, and MCI status. In our pilot studies, we developed an MRI measure of EC length which we validated against histology-based measures. In support of our hypothesis, our 3 year longitudinal pilot data shows that in normal elderly individuals, the reduction in the EC length, is anatomically a unique predictor of cognitive decline to MCI and the reduction of hippocampal volume. We propose to test our hypothesis in a longitudinal study of healthy, cognitively normal elderly, with known risk factors for cognitive decline. We will carefully screen and select three gender balanced groups of community residing volunteers. Group 1 (55-75 years, n=100) will be at increased risk of both brain and cognitive changes on the basis of age and carrying an ApoE-epsilon 4 allele. Group 2 will be comprised of epsilon 4 negative cases (n=100) matched by age and gender with Group 1. Those individuals from both groups greater than 65 year of age will be further selected to equally represent individuals with and without qualitative evidence for hippocampal atrophy. Group 3 will consist of normal subjects (20-30 years, n=40), 50 percent of whom will be epsilon 4 positive. The young group will be used for statistical reference. Over 36 months, all subjects will receive 3 cognitive evaluations and 2 MRI scans. The results will improve our knowledge of the progression of brain changes underlying memory decline in aging.